CN101863824A - 一种含有二氢茚酮并吡咯骨架的化合物的合成方法 - Google Patents
一种含有二氢茚酮并吡咯骨架的化合物的合成方法 Download PDFInfo
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Abstract
本发明涉及一种含有二氢茚酮并吡咯骨架的化合物的合成方法,该方法在有机溶剂和碱的环境中,具有式I结构的化合物与异氰基化合物在铜盐为催化剂的条件下进行串联反应,构建含有二氢茚酮并吡咯骨架分子。所述合成反应的反应条件非常温和,可以以较高产率得到目标化合物。该合成方法,起始原料来源方便,所用催化剂便宜,有实现工业化的前景。
Description
技术领域
本发明属于化学领域,具体是涉及一种合成含有二氢茚酮并吡咯骨架的化合物的合成方法。
背景技术
二氢茚酮并吡咯骨架分子是一类具有多种生物活性的化合物,如抑制5HT2,用于治疗强迫症(J.Med.Chem.1997,40,2762-2769),如抗肿瘤(Indian Journal of Chemistry,SectionB:Organic Chemistry Including Medicinal Chemistry 1988,27(10),957-8),抗病毒活性(Pharmaceutical Chemistry Journal,1987.21(10),725-727),降血糖作用(J.Pharm.Sci.1973,62,1363-1372)等活性,但是合成此类分子存在一定困难。目前报道的一些合成方法产率比较低,起始原料较为复杂(Journal of Heterocyclic Chemistry,1993,30(2),477-82;Synthesis,2006,(5):765-767;Turkish Journal of Chemistry,2009,33,797-802;Pharmaceutical ChemistryJournal,1987.21(10):725-727;Heterocycles,1981,16(1),1-4),因此限制了此类分子作为具有药物活性分子的研究与开发。
发明内容
本发明的目的是提供一种合成含有二氢茚酮并吡咯骨架的化合物的方法,反应条件非常温和,可以以较高产率得到目标化合物。
实现上述目的的技术方案如下:
一种含有二氢茚酮并吡咯骨架的化合物的合成方法,在有机溶剂和碱的环境中,具有式I结构的化合物与异氰基化合物在铜盐为催化剂的条件下进行串联反应,构建含有二氢茚酮并吡咯骨架分子;
式I
其中:
Y为I或Br;
R1选自:
4)C1~C3烷基;
5)NO2,CN,COOMe,COOH,F,Cl,Br等吸电子基团为优选基团;
6)OMe,Me,NH2,NHAc,N,N二烷基(如N,N-二苄基,N,N二乙基);
R2选自:
1)C1~C10烷基;
2)COOMe,COOEt,CO(CH2)n,n=1-10等吸电子基团;
3)苯环或芳香性杂环;
4)被CH3、OMe、N,N二烷基、NH2,NHAc、OH、CN、NO2、CF3、Cl、F、COOR’中一个以上取代基取代的苯环或芳香性杂环;R’为C1~C10烷基;
5)取代芳香性杂环,如吡咯,噻吩,呋喃及取代吡咯,取代噻唑,取代呋喃等。
本发明所述催化剂的量推荐为相对于异氰基化合物的用量的摩尔百分比为3%到20%。
当Y为I时,串联反应的进行温度推荐为20~25℃;当Y为Br时,串联反应的进行温度推荐为60~90℃,尤其推荐在60~70℃之间。
优选地,所述的碱是K2CO3,Cs2CO3,K3PO4,NaOH或KOH或DBU(二氮杂二环,化学名:1.8-二氮杂二环(5.4.0)十一稀-7);所述的有机溶剂推荐为DMSO(二甲基亚砜),DMF(N,N-二甲基甲酰胺),DMA(N,N-二甲基乙酰胺),Dioxane(1,4-二氧六环;)CH3CN等;所述的铜盐是CuI,CuBr,CuCl,CuI2,CuBr2,CuCl2,Cu(OTf)2,或Cu(OTf)2。所述的异氰基化合物为异氰基乙酸乙酯或对甲基苯磺酰甲基异腈。
本发明所述的合成反应的反应条件非常温和,且可以以较高产率得到目标化合物。该合成方法,起始原料来源方便,所用催化剂便宜,有实现工业化的前景。
具体实施方式
通过下述具体实施例将有助于理解本发明,但并不限制本发明的内容。
实施例1
ethyl 3-(4-(diethylamino)phenyl)-4-oxo-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate(1)
3-(4-(二乙胺基)苯基)-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
氩气保护下,室温下((20~25℃)将(E)-3-(4-(二乙氨基)苯基)-1-(2-碘苯基)-2丙烯-1-酮(MW=348,0.5mmol,175mg),异氰基乙酸乙酯(MW=113,0.55mmol,0.06mL),碘化亚铜(0.05mmol,10mg),碳酸铯(MW=325,1.0mmol,325mg)加入到密封的反应管里面,用2mLDMF溶解,室温搅拌24h后,往反应混合液加入10mL水淬灭反应,用10mL乙酸乙酯萃取3次,有机相用无水硫酸钠干燥,减压旋掉溶剂,过硅胶柱分离(淋洗液石油醚∶乙酸乙酯=8∶1),得到108mg产物,产率70%。
1H NMR(CDCl3,400Hz):δ=10.0(br s,1H;NH),7.60(d,J=8.8Hz,2H;Phenyl),7.50(t,1H;Phenyl),7.28(t,1H;Phenyl),7.(dd J=9.2Hz,3.2Hz 2H;Phenyl),6.67(d,J=8.8Hz,2H;Phenyl),4.32(q,J=7.2Hz,2H;OCH2CH3),3.37(q,J=7.2Hz,4H;ArNCH2CH3),1.37(t,J=7.2Hz,3H;OCH2CH3),1.17(t,J=7.2Hz,6H;ArNCH2CH3).
13C NMR(CDCl3,400Hz):δ=186.0(-C=O),161.4(-COOCH2CH3),151.4,147.9,143.1,140.6,133.9,132.7,131.7,129.0,123.6,122.8,121.9,118.5,117.6,110.2,60.6(-OCH2CH3),44.2(NCH2CH3),14.5(-COOCH2CH3),12.6(NCH2CH3)MS(APCI):M/Z:389.1[M+H+].HRMS(EI):calcd for[M+];found:
实施例2
ethyl 3-(4-aminophenyl)-4-oxo-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate(2)
3-(4-氨基苯基)-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
(E)-3-(4-aminophenyl)-1-(2-iodophenyl)prop-2-en-1-one
E-3-(4-氨基苯基)-1-(2-碘苯基)-2-丙烯-1-酮(176mg,0.5mmol)为底物,与异氰基乙酸乙酯(0.55mmol,0.06mL),按实施例1方法,在室温下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:60%。1H NMR(d-DMSO,100Hz:δ=12.64(br s,1H;NH),7..43-7.47(m,4H;Phenyl),7.36(d J=7.2Hz,1H;Phenyl),7.23-7.27(m,1H;Phenyl),6.56(d,J=8.8Hz,2H;Phenyl),5.45(br s,2H;ArNH2),4.23(q,J=7.2Hz,2H;OCH2CH3),1.25(t,J=7.2Hz,3H;OCH2CH3),
13C NMR(d-DMSO,100Hz):δ=185.6(-C=O),160.9(-COOCH2CH3),151.8,149.0,140.4,134.4,133.7,131.6,129.4,123.3,122.2,121.6,119.8.119.0,112.9,60.3(-OCH2CH3),14.6(-COOCH2CH3).MS(APCI):M/Z:333.1[M+H+].
实施例3
ethyl 4-oxo-3-p-tolyl-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate
3-(对甲苯苯基)-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
E-3-(对甲苯苯基)-1-(2-碘苯基)-2-丙烯-1-酮(176mg,0.5mmol)为底物与异氰基乙酸乙酯(0.55mmol,0.06mL),按实施例1方法,在室温下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:70%。
1H NMR(d-DMSO,100Hz):δ=12.82(br s,1H;NH),7.55(d,J=8.0Hz,2H;Phenyl),7.42-7.48(m,2H;Phenyl),7.37(d,J=7.2Hz,2H;Phenyl),7.23-7.27(m,1H;Phenyl),7.18(d,J=8.0Hz,2H;Phenyl),4.23(q,J=7.6Hz,2H;OCH2CH3),2.34(s,3H;ArCH3),1.22(t,J=7.6Hz,3H;OCH2CH3).
13C NMR(d-DMSO,100Hz):δ=185.2(-C=O),160.3(COOCH2CH3),151.5,139.7,137.2,134.0,131.3,133.4,129.9,129.3,129.0,128.5,127.8,123.0,122.9,121.6,119.5,60.1(OCH2CH3),20.9(ArCH3),14.1(COOCH2CH3).MS(APCI):M/Z:332.10M+H+].
实施例4
ethyl 3-(4-methoxyphenyl)-4-oxo-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate
3-(4-甲氧基苯基)-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
E-3-(4-甲氧基苯基)-1-(2-碘苯基)-2-丙烯-1-酮((183mg,0.5mmol))为底物与异氰基乙酸乙酯(0.55mmol,0.06mL),按实施例1方法,在室温下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:60%。
1H NMR(d-DMSO,100Hz):δ=12.80(br s,1H;NH),7.64(d,J=8.4Hz,2H;Phenyl),7.42-7.48(m,2H;Phenyl),7.37(d,J=6.8Hz,1H;Phenyl),7.26(t,J=6.8Hz,1H;Phenyl),6.94(d,J=8.4Hz,2H;Phenyl),4.23(q,J=6.8Hz,2H;OCH2CH3),3.33(s,1H;ArOCH3),1.23(t,J=6.8Hz,3H;OCH2CH3).
13C NMR(d-DMSO,100Hz):δ=185.7(-C=O),160.8(COOCH2CH3),159.5,151.9,140.2,134.4,133.9,131.9,129.8,129.6,124.1,123.4,123.0,121.9,119.9,113.11,60.1(OCH2CH3),,55.5(ArOCH3),14.6(COOCH2CH3).
MS(APCI):M/Z:348.10M+H+].
实施例5
ethyl 3-(naphthalen-1-yl)-4-oxo-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate
3-(萘-1-基)-4-氧代1,4二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
5(E)-1-(2-iodophenyl)-3-(naphthalen-1-yl)prop-2-en-1-one
5(E)-(2-碘苯基)3-(萘-1-基)--2-丙烯-1-酮(192mg,0.5mmol)为底物与异氰基乙酸乙酯(0.55mmol,0.06mL),按实施例1方法,在室温下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:58%。
1H NMR(CDCl3,400Hz):δ=12.80(br s,1H;NH),7.64(d,J=8.4Hz,2H;Phenyl),7.42-7.48(m,2H;Phenyl),7.37(d,J=6.8Hz,1H;Phenyl),7.26(t,J=6.8Hz,1H;Phenyl),6.94(d,J=8.4Hz,2H;Phenyl),4.23(q,J=6.8Hz,2H;OCH2CH3),3.33(s,1H;ArOCH3),1.23(t,J=6.8Hz,3H;OCH2CH3).
13C NMR(d-DMSO,100Hz):δ=185.4(-C=O),160.5(COOCH2CH3),150.3,143.6,140.2,134.4,133.4,132.8,129.1,123.8,123.6,117.5,60.9(OCH2CH3),33.2(C(CH3)3),31.1(C(CH3)3),14.4(COOCH2CH3).MS(APCI):M/Z:298.1M+H+].
实施例6
ethyl 3-(furan-2-yl)-4-oxo-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate
3-(呋喃-2-基)-4-氧代1,4二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
E-3-(呋喃-2-基)-1-(2-碘苯基)-2-丙烯-1-酮(162mg,0.5mmol)为底物与异氰基乙酸乙酯(0.55mmol,0.06mL),按实施例1方法,在室温下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:73%。
1H NMR(CDCl3,400Hz):δ=9.17(br s,1H;NH),7.58(s,1H;Phenyl),7.56(d,J=9.2Hz,1H;Phenyl),7.50(d,j=1H;Phenyl),6.53(dd,J=3.6,2.08Hz,2H;Phenyl),4.41(q,J=7.2Hz,2H;OCH2CH3),1.42(t,J=7.2Hz,3H;OCH2CH3).
13C NMR(d-DMSO,100Hz):δ=184.5(-C=O),160.5(COOCH2CH3),150.9,146.7,142.8,140.2,133.5,132.7,129.4,123.9,122.0,121.9,118.7,118,1,113.4,111.6,61.1(OCH2CH3),14.3(COOCH2CH3).MS(APCI):M/Z:308[M+H+].
实施例7
3,4-二甲基苯基-4-氧代1,4二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
ethyl 3-(3,4-dimethylphenyl)-4-oxo-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate
E-3-(3,4-二甲基苯基)-1-(2-碘苯基)-2-丙烯-1-酮(182mg,0.5mmol)为底物与异氰基乙酸乙酯(0.55mmol,0.06mL),按实施例1方法,在室温下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:43%。
实施例8
ethyl 4-oxo-3-(thiophen-2-yl)-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate
3-(噻吩-2-基)-4-氧代1,4二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
(E)-1-(2-iodophenyl)-3-(thiophen-2-yl)prop-2-en-1-one
E-3-(噻吩-2-基)-1-(2-碘苯基)-2-丙烯-1-酮(170mg,0.5mmol)为底物与异氰基乙酸乙酯(0.55mmol,0.06mL),按实施例1方法,在室温下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:55%。
1H NMR(CDCl3,400Hz):δ=9.53(br s,1H;NH),8.36(dd,J=2.4Hz,0.8Hz,1H;Phenyl),7.95(dd,j=4.0Hz,0.8Hz,1H;Phenyl),6.53(d,J=6.0Hz,2H;Phenyl),7.31-7.37(m,2H;Phenyl),7.24(d,J=6.0Hz,1H;Phenyl),7.18(d,J=5.6Hz,1H;Phenyl),4.38(q,J=5.6Hz,2H;OCH2CH3),1.40(t,J=5.6Hz,3H;OCH2CH3).
13C NMR(d-DMSO,100Hz):δ=185.6(-C=O),160.6(COOCH2CH3),151.0,140.2,142.8,140.2,133.5,132.9,131.5,130.0,129.4,127.8,125.1,124.0,123.9123.0,122.5,122.5,118.2,61.1(OCH2CH3),14.4(COOCH2CH3).MS(APCI):M/Z:324.0[M+H+].
实施例9
ethyl 3-(3-hydroxy-4-methoxyphenyl)-4-oxo-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate
3-(3羟基4-甲氧基苯基)-4-氧代1,4二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
E-3-(3羟基4-甲氧基苯基)-1-(2-碘苯基)-2-丙烯-1-酮(190mg,0.5mmol)为底物与异氰基乙酸乙酯(0.55mmol,0.06mL),按实施例1方法,在室温下搅拌24小时。粗产物经层析(10∶1石油醚∶乙酸乙酯)提纯,产率:20%。
1H NMR(d-DMSO,100Hz):δ=12.76(br s,1H;NH),8.91(br s,1H;ArOH),7.42(m,2H;Phenyl),7.37(d,J=7.2Hz,1H;Phenyl),7.24-7.28(m,1H;Phenyl),7.10-7.13(m,2H;Phenyl),6.91(d,J=8.4Hz,1H;Phenyl),4.22(q,J=7.2Hz,2H;OCH2CH3),3.81(s,3H;ArOCH3),1.23(t,J=7.2Hz,3H;OCH2CH3).MS(APCI):M/Z:364.0[M+H+]。
实施例10
ethyl 3-(1-methyl-1H-pyrrol-2-yl)-4-oxo-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate
3-(1-甲基-1H-吡咯-2-基)-4-氧代1,4二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
E-3-(1-甲基-1H-吡咯-2-基)-1-(2-碘苯基)-2-丙烯-1-酮(167mg,0.5mmol)为底物与异氰、基乙酸乙酯(0.55mmol,0.06mL),按实施例1方法,在室温下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:45%。
1H NMR(CDCl3,400Hz):δ=9.73(br s,1H;NH),7.51(d,J=6.8,1H;Phenyl),7.35(t,j=7.2Hz,1H;Phenyl),7.20-7.25(m,2H;Phenyl),6.75(s,1H;Phenyl),6.40(d,J=3.6Hz,1H;Phenyl),6.19(d,J=3.6Hz,1H;Phenyl),4.29(q,J=7.2Hz,2H;OCH2CH3),1.28(t,J=7.2Hz,3H;OCH2CH3).
MS(APCI):M/Z:324.0[M+H+]。
实施例11
ethyl 3-(4-methylthiophen-2-yl)-4-oxo-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate
3-(-4-甲基噻吩-2-基)-4-氧代1,4二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
E-3-(-4-甲基噻吩-2-基)-1-(2-碘苯基)-2-丙烯-1-酮(176mg,0.5mmol)为底物与异氰基乙酸乙酯(0.55mmol,0.06mL),按实施例1方法,在室温下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:55%。
1H NMR(CDCl3,400Hz):δ=10.00(br s,1H;NH),7.59(d,J=7.2Hz,1H;Phenyl),7.33(t,j=7.2Hz,1H;Phenyl),7.20-7.27(m,3H;Phenyl),6.90(d,J=4.2Hz,1H;Phenyl),4.27(q,J=7.2Hz,2H;OCH2CH3),1.23(t,J=7.2Hz,3H;OCH2CH3).
13C NMR(d-DMSO,100Hz):δ=185.4(-C=O),161.2(COOCH2CH3),151.2,140.1,137.2,134.0,132.9,129.5,129.3,127.3,124.9,124.8,124.6,123.8,121.1,118.5,61.1(OCH2CH3),14.8(ArCH3).14.0(COOCH2CH3).MS(APCI):M/Z:338.0[M+H+]。
实施例12
ethyl 4-oxo-3-m-tolyl-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate
3-(-3-甲基苯基)-4-氧代1,4二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
E-3-(-3-甲基苯基)-1-(2-碘苯基)-2-丙烯-1-酮(174mg,0.5mmol)为底物与异氰基乙酸乙酯(0.55mmol,0.06mL),按实施例1方法,在室温下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:45%。
1H NMR(d-DMSO,100Hz):δ=10.10(br s,1H;NH),7.48-7.54(m,3H;Phenyl),7.30(t,j-7.2Hz,2H;Phenyl),7.14-7.23(m,3H;Phenyl),4.29(q,J=7.2Hz,2H;OCH2CH3),2.39(s,3H;ArCH3),1.26(t,J=7.2Hz,3H;OCH2CH3).
13C NMR(d-DMSO,100Hz):δ=185.9(-C=O),161.5(COOCH2CH3),151.3,140.3,136.9,134.0,132.9,131.0,130.9,130.6,129.3,127.4,123.8,123.4,123.2,118.4,61.0(OCH2CH3),21.4(ArCH3),14.1(COOCH2CH3).MS(APCI):M/Z:332.10M+H+]。
实施例13
3-(-3-甲氧苯基)-4-氧代1,4二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
ethyl 3-(3-methoxyphenyl)-4-oxo-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate
E-3-(-3-甲氧苯基)-1-(2-碘苯基)-2-丙烯-1-酮(183mg,0.5mmol)为底物与异氰基乙酸乙酯(0.55mmol,0.06mL),按实施例1方法,在室温下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:59%。
1H NMR(d-DMSO,100Hz):δ=12.88(br s,1H;NH),7.46(d,J=6.4Hz,2H;Phenyl),7.38(d,J=7.2Hz,1H;Phenyl),7.23-7.31(m,4H;Phenyl),6.92(d,J=7.2Hz,2H;Phenyl),4.22(q,J=7.2Hz,2H;OCH2CH3),3.79(s,3H;ArOCH3),1.21(t,J=7.2Hz,3H;OCH2CH3).
13C NMR(d-DMSO,100Hz):δ=185.2(-C=O),160.3(COOCH2CH3),158.3,151.6,139.7,134.0,133.5,132.7,129.1,128.2,123.0,122.4,121.7,119.5,115.2.,113.6,60.1(OCH2CH3),55.0(ArOCH3),14.0(COOCH2CH3).MS(APCI):M/Z:348.0M+H+].
实施例14
3-苯基-4-氧代1,4二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
ethyl 4-oxo-3-phenyl-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate
E-3-苯基-1-(2-碘苯基)-2-丙烯-1-酮(166mg,0.5mmol)为底物与异氰基乙酸乙酯(0.55mmol,0.06mL),按实施例1方法,在室温下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:59%。
1H NMR(CDCl3,400Hz):δ=9.55(br s,1H;NH),7.74(d,J=6.8Hz,2H;Phenyl),7.51(d,J=7.2Hz,1H;Phenyl),7.33-7.44(m,4H;Phenyl),7.23(d,J=7.2Hz,1H;Phenyl),7.18(d,J=7.2Hz,1H;Phenyl)4.30(q,J=7.2Hz,2H;OCH2CH3),1.28(t,J=7.2Hz,3H;OCH2CH3).MS(APCI):M/Z:[M+H+].
实施例15
ethyl 3-(4-tert-butylphenyl)-4-oxo-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate
3-(4-叔丁基苯基)-4-氧代1,4二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
E-3-(4-叔丁基苯基)-1-(2-碘苯基)-2-丙烯-1-酮(193mg,0.5mmol)为底物与异氰基乙酸乙酯(0.55mmol,0.06mL),按实施例1方法,在室温下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:46%。
1H NMR(CDCl3,400Hz):δ=9.95(br s,1H;NH),7.71(d,J=8.4Hz,2H;Phenyl),7.50(d,J=7.2Hz,1H;Phenyl),7.20(d,J=8.4Hz,2H;Phenyl),7.30-7.34(m,1H;Phenyl),7.18-7.23(m,2H;Phenyl),4.31(q,J=7.2Hz,2H;OCH2CH3),1.34(s,3H;ArC(CH3)3),1.28(t,J=7.2Hz,3H;OCH2CH3).
13C NMR(CDCl3,400Hz):δ=185.6(-C=O),161.1(COOCH2CH3),151.4,151.1,140.4,133.9,132.8,130.8,133.4,130.0,129.3,129.2,124.4,123.8,123.5,123.1,118.1,60.9(OCH2CH3),34.7(ArC(CH3)3),31.3(ArC(CH3)3),14.1(COOCH2CH3).
MS(APCI):M/Z:332.10M+H+].
实施例16
ethyl 3-(4-acetamidophenyl)-4-oxo-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate
3-(4-乙酰胺基苯基)-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
E-N-(4-(3-(2-碘苯基)-3-氧代丙烯基)苯基)乙酰胺(196mg,0.5mmol)为底物与异氰基乙酸乙酯(0.06mL,0.55mmol),按实施例1方法,在室温下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:42%。
1H NMR(d-DMSO,100Hz):δ=12.83(br s,1H;NH),10.03(br s,1H;NHCOCH3)7.60(dd,J=8.4Hz,4H;Phenyl),7.44(t,2H;Phenyl),7.37(d,J=7.2Hz,1H;Phenyl),7.26(t,1H;Phenyl)4.22(q,J=6.8Hz,2H;OCH2CH3),2.07(s,1H;COCH3)1.22(t,J=6.8Hz,3H;OCH2CH3).
13C NMR(d-DMSO,100Hz):δ=185.7(-C=O),168.7(CH3CONH-),160.8(-COOCH2CH3),151.9,140.2,139.5,134.4,133.9,131.0,129.6,126.4,123.2,122.0,119.9,118.1,60.6(-OCH2CH3),24.5(CH3CONH-)14.5(-COOCH2CH3).
MS(APCI):M/Z:375.0[M+H+].
实施例17
3-(4-氯苯基)-4-氧代1,4二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
E-3-(4-氯苯基)-1-(2-碘苯基)-2-丙烯-1-酮(182mg,0.5mmol)为底物与异氰基乙酸乙酯(0.06mL,0.55mmol),按实施例1方法,在室温下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:30%。
1H NMR(d-DMSO,100Hz):δ=12.93(br s,1H;NH),7.67(d,J=8.0Hz,2H;Phenyl),7.44(d,J=8.0Hz,4H;Phenyl),7.37(d,J=6.8Hz,1H;Phenyl),7.26(s,1H;Phenyl),4.22(q,J=6.8Hz,2H;OCH2CH3),1.21(t,J=6.8Hz,3H;OCH2CH3).
13C NMR(d-DMSO,100Hz):δ=185.2(-C=O),160.1(COOCH2CH3),151.6,139.5,140.0,133.6,132.5,131.8,130.4,129.2,127.6,123.2,123.1,121.6,119.6,60.3(OCH2CH3),14.0(COOCH2CH3).
MS(APCI):M/Z:352.0M+H+].
实施例18
ethyl 3-(4-nitrophenyl)-4-oxo-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate
3-(4-硝基苯基)-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
以E-3-(硝基苯基)-1-(2-碘苯基)-2-丙烯-1-酮(189mg,0.5mmol)为底物与异氰基乙酸乙酯(0.06mL,0.55mmol),按实施例1方法,在室温下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:41%。
1H NMR(d-DMSO,100Hz):δ=13.11(br s,1H;NH),8.24(d,J=8.8Hz,2H;Phenyl),7.91(d,J=8.8Hz,2H;Phenyl),7.48(t,2H;Phenyl),7.40(d,J=8.8Hz,1H;Phenyl),7.27-7.30(m,1H;Phenyl),4.23(q,J=7.2Hz,2H;OCH2CH3),1.21(t,J=7.2Hz,3H;OCH2CH3).
13C NMR(d-DMSO,100Hz):δ=185.6(-C=O),160.4(-COOCH2CH3),152.2,147.1,139.8,139.0,134.4,134.2,131.7,129.8,126.6,124.4,123.7,122.9122.2,120.2,61.0(-OCH2CH3),14.4(-COOCH2CH3).
MS(APCI):M/Z:362.0[M+H+].
HRMS(EI):calcd for[M+];found:
实施例19
ethyl 3-(4-cyanophenyl)-4-oxo-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate(19)
3-(4-氰基苯基)-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
以E-4-(2-碘苯基)-3-氧代丙烯苯腈(180mg,0.5mmol)为底物与异氰基乙酸乙酯(0.06mL,0.55mmol),按实施例1方法,在室温下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:38%。
1H NMR(d-DMSO,100Hz):δ=13.08(br s,1H;NH),7.84(dd,J=13.68.4Hz,4H;Phenyl),7.46(d,J=12.4Hz,1H;Phenyl),7.39(d,J=6.8Hz,1H;Phenyl),7.29(t,1H;Phenyl),4.23(q,J=7.2Hz,2H;OCH2CH3),1.21(t,J=7.2Hz,3H;OCH2CH3).
13C NMR(d-DMSO,100Hz):δ=185.6(-C=O),160.4(-COOCH2CH3),152.2,139.9,137.0,134.4,134.2,131.7,131.3,129.8,127.2,124.2,123.7,122.1,120.1,119.3,110.7,60.9(-OCH2CH3),14.4(-COOCH2CH3).MS(APCI):M/Z:342.0[M+H+].
实施例20
3-(2-氯嘧啶-3-基)-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
以E-3-(2-氯嘧啶-3-基)-1-(2-碘苯基)-2-丙烯-1-酮(180mg,0.5mmol)为底物与异氰基乙酸乙酯(0.06mL,0.55mmol),按实施例1方法,在室温下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:55%。
1H NMR(CDCl3,400Hz):δ=10.26(br s,1H;NH),8.41(s,1H;Phenyl),7.77(d,J=7.2Hz,1H;Phenyl),7.49(d,J=7.2Hz,1H;Phenyl),7.36(t,J=7.2Hz,1H;Phenyl),7.30(d,J=7.2Hz,1H;Phenyl),7.23(d,J=9.2Hz,2H;Phenyl),4.20(q,J=6.8Hz,2H;OCH2CH3),1.10(t,J=6.8Hz,3H;OCH2CH3).
13C NMR(d-DMSO,100Hz):δ=185.42(-C=O),160.4(COOCH2CH3),151.9,149.9,149.2,141.2,139.8,134.8,134.2,129.8,125.6,123.7,123.1,122.8,120.1,60.7(OCH2CH3),14.3(COOCH2CH3).MS(APCI):M/Z:353.0[M+H+].
实施例21
3-甲基-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
Ethyl3-methyl-4-oxo-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate
(E)-1-(2-碘苯-)丁基-2-烯-1-酮以(150mg,0.5mmol)为底物与异氰基乙酸乙酯(0.06mL,0.55mmol),按实施例1方法,在室温下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:15%。
1H NMR(CDCl3,400Hz):δ=9.96(br s,1H;NH),7.45(d,J=7.2Hz,1H;Phenyl),7.28(d,J=7.2Hz,1H;Phenyl),7.16-7.20(s,2H;Phenyl),4.37(q,J=7.2Hz,2H;OCH2CH3),2.45(s,3H;CH3),1.40(t,J=7.2Hz,3H;OCH2CH3).
13C NMR(CDCl3,400Hz)δ=187.0(-C=O),162.1(COOCH2CH3),151.0,140.5,134.3,132.8,129.0,127.0,124.9,123.6,118.3,60.8(OCH2CH3),14.4(COOCH2CH3),11.3(CH3)
实施例22
ethyl 3-tert-butyl-4-oxo-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate
3-叔丁基-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
(E)-1-(2-碘苯-)4,4二甲基-3-戊-烯-1-酮以(158mg,0.5mmol)为底物与异氰基乙酸乙酯(0.06mL,0.55mmol),按实施例1方法,在室温下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:30%。
1H NMR(CDCl3,400Hz):δ=9.62(br s,1H;NH),7.46(d,J=7.2Hz,1H;Phenyl),7.30(t,1H;Phenyl),7.19(t,1H;Phenyl),7.19(d,J=7.2Hz,1H;Phenyl),4.37(q,J=7.2Hz,2H;OCH2CH3),1.51(s,9H;C(CH3)3),1.40(t,J=7.2Hz,3H;OCH2CH3).
13C NMR(CDCl3,400Hz)185.4(-C=O),160.5(COOCH2CH3),150.3,143.6,140.2,134.4,133.4,132.8,129.1,123.8,123.6,117.5,60.9(OCH2CH3),33.2(C(CH3)3),31.1(C(CH3)3),14.4(COOCH2CH3).
实施例23
3-环己基-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
ethyl 3-cyclohexyl-4-oxo-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate
(E)-1-(2-碘苯-)3-环己基-2-烯-1-酮以(170mg,0.5mmol)为底物与异氰基乙酸乙酯(0.06mL,0.55mmol),按实施例1方法,在室温下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:30%。
13C NMR(CDCl3,400Hz)δ=185.8(-C=O),161.9(COOCH2CH3),151.8,140.3,139.1,134.2,132.7,129.1,123.6,123.0,117.9,60.7(OCH2CH3),35.9,32.5,26.7,25.8,14.4(COOCH2CH3).
实施例24
4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-3二羧酸二乙酯
diethyl 4-oxo-1,4-dihydroindeno[1,2-b]pyrrole-2,3-dicarboxylate
(E)-4(2-碘苯-)-4-氧代丁基-2-烯酸乙酯以(165mg,0.5mmol)为底物与异氰基乙酸乙酯(0.06mL,0.55mmol),按实施例1方法,在室温下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:30%。
1H NMR(CDCl3,400Hz):δ=10.12(br s,1H;NH),7.50(d,J=6.8Hz,1H;Phenyl),7.32-7.36(m,1H;Phenyl),7.22-7.25(m,1H;Phenyl),7.19(d,J=7.2Hz,1H;Phenyl),4.35-7.44(m,4H;OCH2CH3),1.13-1.43(m,6H;OCH2CH3).
13C NMR(CDCl3,400Hz)δ=184.3(-C=O),163.0(COOCH2CH3),160.3(COOCH2CH3),150.6,139.4,133.1,129.6,126.3,124.1,123.5,118.6,118.3,61.7(OCH2CH3),61.7(OCH2CH3),14.1(COOCH2CH3),14.1(COOCH2CH3).
实施例25
2-乙基-7-甲基-4-氧代-3-对甲苯基1,4-二氢茚酮[1,2-b]吡咯-2,7-二羧酸酯
以(E)3-碘-4(3-对甲苯基丙烯酰基)苯甲酸甲酯(MW=406,203mg,0.05mo1)以为底物,与异氰基乙
乙酯(MW=113,0.06Ml,0.55mol)在如实施例1方法反应24h.粗产物经柱层析(6∶1石油醚∶乙酸乙酯)提纯,产率:75%。
1H NMR(d-DMSO,400Hz):δ=12.88(br s,1H;NH),8.05(s,1H;Phenyl),7.88(dd,J=7.6Hz,1H;Phenyl),7.56(d,J=8.0Hz,2H;Phenyl),7.49(d,J=7.6Hz,1H;Phenyl),7.19(d,J=8.0Hz,2H;Phenyl),4.22(m,J=7.2Hz,2H;OCH2CH3),2.35(s,3H;ArCH3),1.24(t,J=7.2Hz,3H;OCH2CH3).
13C NMR(d-DMSO,100Hz):δ=184.5(-C=O),165.9(COOCH3),160.6(COOCH2CH3),151.1,144.0,137.9,134.9,131.3,130.4,129.9,128.8,124.0,123.4,122.8,120.0,60.7(OCH2CH3),52.9(COOCH3),21.4(ArCH3),14.5(COOCH2CH3).
MS(APCI):M/Z:390.0[M+H+].HRMS(EI):calcd for[M+];found:
实施例26
2-ethyl-7-methyl-4-oxo-3-(3,4,5-trimethoxyphenyl)-1,4-dihydroindeno[1,2-b]pyrrole-2,7-dicarboxylate
2-乙基-7-甲基4-氧代-3-(3-4,5三甲氧基苯)-1,4-二氢茚酮[1,2-b]吡咯-2,7-二羧酸酯
(E)3-碘-4(3-4,5三甲氧基苯基丙烯酰基)苯甲酸甲酯(241mg,0.05mol)以为底物,与异氰基乙酸乙酯(0.06mL,0.55mol)在如实施例1方法反应24h.粗产物经柱层析(6∶1石油醚∶乙酸乙酯)提纯,产率:77%。
13C NMR(d-DMSO,100Hz):δ=184.5(-C=O),165.8(COOCH3),160.5(COOCH2CH3),152.1,151.0,143.8,138.0,134.6,131.3,130.0,126.8,123.8,123.5,122.6,120.1,108.4,60.8(ArOCH3),60.5(ArOCH3)56.3(ArOCH3),52.9(OCH2CH3),14.6(COOCH2CH3).
MS(APCI):M/Z:390.0[M+H+].HRMS(EI):calcd for[M+];found:
实施例27
2-乙基-7-甲基-4-氧代-3-苯基1,4-二氢茚酮[1,2-b]吡咯-2,7-二羧酸酯
2-ethyl 7-methyl 4-oxo-3-phenyl-1,4-dihydroindeno[1,2-b]pyrrole-2,7-dicarboxylate
以(E)3-碘-4-肉桂酰基苯甲酸甲酯(196mg,0.05mol)以为底物,与异氰基乙乙酯(0.06mL,0.55mol)在如实施例1方法反应24h.粗产物经柱层析(6∶1石油醚∶乙酸乙酯)提纯,产率:70%。
1H NMR(d-DMSO,400Hz):δ=12.88(br s,1H;NH),8.04(s,1H;Phenyl),7.84(d,J=6.0Hz,1H;Phenyl),7.64(d,J=5.6Hz,2H;Phenyl),7.45(d,J=6.0Hz,1H;Phenyl),7.33-7.39(m,3H;Phenyl),4.21(m,J=5.6Hz,2H;OCH2CH3),1.22(t,J=5.6Hz,3H;OCH2CH3).
13CNMR(d-DMSO,100Hz):δ=184.5(-C=O),165.7(COOCH3),160.5(COOCH2CH3),151.1,143.8,134.8,134.2,131.7,131.3,130.4,129.6,128.4,127.7,124.1,123.4,122.7,120.0,60.7(OCH2CH3),52.9(COOCH3),14.4(COOCH2CH3).
MS(APCI):M/Z:390.0[M+H+
实施例28
2-乙基-7-氰基-4-氧代-3-对甲苯基1,4-二氢茚酮[1,2-b]吡咯-2羧酸乙酯酯
ethyl 7-cyano-4-oxo-3-p-tolyl-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate
以(E)3-碘-4-(3对甲苯基丙烯酰基)苯氰(187mg,0.05mol)以为底物,与异氰基乙酸乙酯(0.06mL,0.55mol)在如实施例1方法反应24h.粗产物经柱层析(6∶1石油醚∶乙酸乙酯)提纯,产率:60%。1H NMR(d-DMSO,100Hz):δ=12.93(br s,1H;NH),7.76(dd,j=7.2Hz,1.6Hz,1H;Phenyl),7.68(s,1H;Phenyl),7.49-7.55(m,3H;Phenyl),7.19(d,J=8.0Hz,1H;Phenyl),4.23(q,J=7.2Hz,2H;OCH2CH3),2.34(ArCH3),1.22(t,J=7.2Hz,3H;OCH2CH3).13C NMR(d-DMSO,100Hz):δ=183.8(-C=O),160.7(COOCH2CH3),150.4,143.7,138.1,135.2,134.9,130.5,130.0,129.8,128.7,125.5,124.4,124.0,122.9,122.1,118.8,115.8,61.0(OCH2CH3),21.5(ArCH3)14.7(COOCH2CH3).
MS(APCI):M/Z:396.0[M+H+].
HRMS(EI):calcd for[M+];found:
实施例29
7-硝基-4-氧代-3-对甲苯基1,4-二氢茚酮[1,2-b]吡咯-2羧酸乙酯酯
以E-3-对甲苯基-1-(2-碘-4-硝基苯基)-2-丙烯-1-酮(197mg,0.05mol)以为底物,与异氰基乙酸乙酯(0.06mL,0.55mol)在如实施例1方法反应24h.粗产物经柱层析(6∶1石油醚∶乙酸乙酯)提纯,产率:75%。
13C NMR(d-DMSO,100Hz):δ=183.1(-C=O),160.4(COOCH2CH3),149.6,144.9,137.9,135.6,130.3,129.8,128.4,125.5,124.4,123.9,123.3,114.2,60.8(OCH2CH3),21.3(ArCH3)14.4(COOCH2CH3).
MS(APCI):M/Z:396.0[M+H+].
HRMS(EI):calcd for[M+];found:
实施例30
ethyl 7-chloro-4-oxo-3-p-tolyl-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate
7-氯-4-氧代-3-对甲苯基1,4-二氢茚酮[1,2-b]吡咯-2羧酸乙酯酯
以E-3-对甲苯基-1-(2-碘-4-氯苯基)-2-丙烯-1-酮(190mg,0.05mol)以为底物,与异氰基乙酸乙酯(0.06mL,0.55mol)在如实施例1方法反应24h.粗产物经柱层析(6∶1石油醚∶乙酸乙酯)提纯,产率:57%。1H NMR(CDCl3,400Hz):δ=10.9(br s,1H;NH),7.62(d,J=8.0Hz,2H;Phenyl),7.42(d,J=8.0Hz,2H;Phenyl),7.19-7.24(m,4H;Phenyl),4.33(q,J=7.2Hz,2H;OCH2CH3),2.39(s,3H;ArCH3),1.30(t,J=7.2Hz,3H;OCH2CH3).
13C NMR(DMSO,100Hz):δ=184.3(-C=O),160.6(COOCH2CH3),150.0,138.6,138.3,137.8,136.4,130.4,,129.8,128.9,128.7,124.9,123.8,122.7,120.0,60.7(OCH2CH3),52.9(COOCH3),21.3(ArCH3),14.5(COOCH2CH3).
MS(APCI):M/Z:366.1[M+H+].
实施例31
ethyl 7-fluoro-4-oxo-3-p-tolyl-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate
7-氟-4-氧代-3-对甲苯基1,4-二氢茚酮[1,2-b]吡咯-2羧酸乙酯酯
以E-3-对甲苯基-1-(2-碘-4-氟苯基)-2-丙烯-1-酮(183mg,0.05mol)以为底物,与异氰基乙酸乙酯(0.06mL,0.55mol)在如实施例1方法反应24h.粗产物经柱层析(6∶1石油醚∶乙酸乙酯)提纯,产率:42%。
1H NMR(CDCl3,400Hz):δ=10.11(br s,1H;NH),7.61(d,J=7.6Hz,2H;Phenyl),7.47(dd,J=8.0Hz,1.2Hz,1H;Phenyl),7.20(d,J=7.6Hz,2H;Phenyl),6.95(dd,J=8.0Hz,1.2Hz,1H;Phenyl),6.84-6.88(m,1H;Phenyl),4.31(q,J=7.2Hz,2H;OCH2CH3),2.38(s,3H;ArCH3),1.28(t,J=7.2Hz,3H;OCH2CH3).
MS(APCI):M/Z:350.1[M+H+].
实施例32
ethyl 6-nitro-4-oxo-3-p-tolyl-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate
氩气保护下,E-1-(2-溴-5-硝基苯基)-3-对甲苯基-2-丙烯-1-酮(173mg,0.5mmol)为底物与异氰基乙酸乙酯(0.06mL,0.55mol),碘化亚铜(0.05mmol,10mg),碳酸铯(1.0mmol,325mg)加入到密封的反应管里面,用2mLDMF溶解,在80℃下搅拌24小时,往反应混合液加入10mL水淬灭反应,用10mL乙酸乙酯萃取3次,有机相用无水硫酸钠干燥,减压旋掉溶剂。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:38%。
1H NMR(d-DMSO,100Hz):δ=13.18(br s,1H;NH),8.40(dd,J=8.0Hz,1.6Hz,1H;Phenyl),7.96(d,J=2.4Hz,1H;Phenyl),7.55(d,J=8.0Hz,1H;Phenyl),7.21(d,J=8.0Hz,1H;Phenyl),4.24(q,J=7.2Hz,2H;OCH2CH3),2.35(s,3H;ArCH3)1.22(t,J=7.2Hz,3H;OCH2CH3).MS(APCI):M/Z:379.1[M+H+].
实施例33
ethyl 6-bromo-4-oxo-3-phenyl-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate(36)
3-苯基-4-氧代-6溴-1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯(36)
E-1-(2,5-二溴苯基)-3-苯基-2-丙烯-1-酮(181mg,0.5mmol)为底物与异氰基乙酸乙酯(0.06mL),按实施例32方法,在70℃下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:40%。
1H NMR(d-DMSO,100Hz):δ=12.86(br s,1H;NH),7.63(m,3H;Phenyl),7.46(dd,J=7.6Hz,1H;Phenyl),7.38(m,3H;Phenyl),7.29(d,J=8.0Hz,1H;Phenyl),4.21(q,J=7.2Hz,2H;OCH2CH3),1.20(t,J=7.2Hz,3H;OCH2CH3).13C NMR(d-DMSO,100Hz):δ=184.5(-C=O),160.6(COOCH2CH3),150.1,138.9,136.4,140.0,131.6,130.4,129.6,128.4,125.2,124.1,122.8,122.6,60.7(OCH2CH3),14.4(COOCH2CH3).
MS(APCI):M/Z:396.0[M+H+].
HRMS(EI):calcd for[M+];found:
实施例34
2-乙基-7-甲基-4-氧代-3-对甲苯基1,4-二氢茚酮[1,2-b]吡咯-2,7-二羧酸酯
(E)3-碘-4(3-对甲苯基丙烯酰基)苯甲酸甲酯((179mg,0.5mmol)为底物与异氰基乙酸乙酯(0.06mL),按实施例32方法,在70℃下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:38%。
1H NMR(d-DMSO,100Hz):δ=12.88(br s,1H;NH),8.05(s,1H;Phenyl),7.88(dd,J=7.6Hz,1H;Phenyl),7.56(d,J=8.0Hz,2H;Phenyl),7.49(d,J=7.6Hz,1H;Phenyl),7.19(d,J=8.0Hz,2H;Phenyl),4.22(m,J=7.2Hz,2H;OCH2CH3),2.35(s,3H;ArCH3),1.24(t,J=7.2Hz,3H;OCH2CH3).
13C NMR(d-DMSO,100Hz):δ=184.5(-C=O),165.9(COOCH3),160.6(COOCH2CH3),151.1,144.0,137.9,134.9,131.3,130.4,129.9,128.8,124.0,123.4,122.8,120.0,60.7(OCH2CH3),52.9(COOCH3),21.4(ArCH3),14.5(COOCH2CH3).
MS(APCI):M/Z:390.0[M+H+].
HRMS(EI):calcd for[M+];found:
实施例35
4-氧代-3-对甲苯基-1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯()
E-1-(2-溴苯基)-3-对甲苯基-2-丙烯-1-酮(150mg,0.5mmol)为底物与异氰基乙酸乙酯(0.06mL),按实施例32方法,在80℃下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:25%。
1H NMR(d-DMSO,100Hz):δ=12.82(br s,1H;NH),7.55(d,J=8.0Hz,2H;Phenyl),7.42-7.48(m,2H;Phenyl),7.37(d,J=7.2Hz,2H;Phenyl),7.23-7.27(m,1H;Phenyl),7.18(d,J=8.0Hz,2H;Phenyl),4.23(q,J=7.6Hz,2H;OCH2CH3),2.34(s,3H;ArCH3),1.22(t,J=7.6Hz,3H;OCH2CH3).
13C NMR(d-DMSO,100Hz):δ=185.2(-C=O),160.3(COOCH2CH3),151.5,139.7,137.2,134.0,131.3,133.4,129.9,129.3,129.0,128.5,127.8,123.0,122.9,121.6,119.5,60.1(OCH2CH3),20.9(ArCH3),14.1(COOCH2CH3).MS(APCI):M/Z:332.10M+H+].
实施例36
4-氧代-3-(4-氯苯基)-1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
E-1-(2-溴苯基)-3(-4-氯苯基)-2-丙烯-1-酮(161mg,0.5mmol)为底物与异氰基乙酸乙酯(0.06mL),按实施例32方法,在80℃下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:15%。
1H NMR(d-DMSO,100Hz):δ=12.93(br s,1H;NH),7.67(d,J=8.0Hz,2H;Phenyl),7.44(d,J=8.0Hz,4H;Phenyl),7.37(d,J=6.8Hz,1H;Phenyl),7.26(s,1H;Phenyl),4.22(q,J=6.8Hz,2H;OCH2CH3),1.21(t,J=6.8Hz,3H;OCH2CH3).
13C NMR(d-DMSO,100Hz):δ=185.2(-C=O),160.1(COOCH2CH3),151.6,139.5,140.0,133.6,132.5,131.8,130.4,129.2,127.6,123.2,123.1,121.6,119.6,60.3(OCH2CH3),14.0(COOCH2CH3).
MS(APCI):M/Z:352.0M+H+].
实施例37
4-氧代-3-(4-三氟甲基苯基)-1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
氩气保护下,E-3-(4-三氟甲基苯基)-1-(2-碘苯基)-2-丙烯-1-酮为底物与异氰基乙酸乙酯(0.06mL),碘化亚铜(0.05mmol,10mg),碳酸铯(1.0mmol,325mg)加入到密封的反应管里面,用2mLDMF溶解,在60℃下搅拌24小时,往反应混合液加入10mL水淬灭反应,用10mL乙酸乙酯萃取3次,有机相用无水硫酸钠干燥,减压旋掉溶剂。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:37%。1H NMR(d-DMSO,100Hz):δ=13.02(br s,1H;NH),7.84(d,J=8.4,2H;Phenyl),7.74(d,J=8.4Hz,2H;Phenyl),7.47(t,2H;Phenyl),7.38(d,J=7.2Hz,1H;Phenyl),7.25-7.29(m,1H;Phenyl),4.21(q,J=7.2Hz,2H;OCH2CH3),1.19(t,J=7.2Hz,3H;OCH2CH3).
实施例38
7-氨基-4-氧代-3-(对甲基苯基)-1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
Ethyl 7-amino-4-oxo-3-p-tolyl-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate
E-1-(4-氨基2-碘苯基)-3(-4-对甲苯基)-2-丙烯-1-酮(181mg,0.5mmol)为底物与异氰基乙酸乙酯(0.06mL),按实施例37方法,在60℃下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:15%。
1H NMR(CDCl3,400Hz):δ=12.66(br s,1H;NH),7.53(d,J=8.0Hz,2H;Phenyl),7.16(t,2H;Phenyl),7.07(d,J=8.0Hz,1H;Phenyl),6.72(d,J=1.6Hz,1H;Phenyl),6.24(dd,J=8.0Hz,2.0Hz,1H;Phenyl),6.19(s,2H;ArNH2),4.19(q,J=7.2Hz,2H;OCH2CH3),2.33(s,3H;ArCH3),1.21(t,J=7.2Hz,3H;OCH2CH3).
实施例40
7-(N,N-二苄基氨基)-4-氧代-3-(对甲基苯基)-1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
(E)-1-(4-(dibenzylamino)-2-iodophenyl)-3-p-tolylprop-2-en-1-one
E-1-(4-(4-N,N-二苄基氨基)-2-碘苯基)-3-对甲苯基-2-丙烯-1-酮(310mg,0.5mmol)为底物与异氰基乙酸乙酯(0.06mL),按实施例37方法,在60℃下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:33%。
1H NMR(d-DMSO,100Hz):δ=12.58(br s,1H;NH),7.52(d,J=8.0Hz,2H;Phenyl),7.37(t,J=7.2Hz,4H;Phenyl),7.28(d,J=7.6Hz,6H;Phenyl),7.14(t,J=8.0Hz,3H;Phenyl),7.07(s,1H;Phenyl),6.35(d,J=8.0Hz,1H;Phenyl),4.78(s,4H;PhCH2),4.17(q,J=6.8Hz,2H;OCH2CH3),2.33(s,3H;ArCH3),1.18(t,J=6.8Hz,3H;OCH2CH3).
13C NMR(d-DMSO,100Hz):δ=185.2(-C=O),160.8(COOCH2CH3),153.1,138.1,1373,136.8,130.5,130.5,,129.3,128.2,127.5,127.0,125.4,123.6,122.4,109.6,104.9,60.3(OCH2CH3),54.2(PhCH2),21.3(ArCH3),14.6(COOCH2CH3).MS(APCI):M/Z:[M+H+].
实施例41
7-乙酰氨基-4-氧代-3-(对甲基苯基)-1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
ethyl 7-acetamido-4-oxo-3-p-tolyl-1,4-dihydroindeno[1,2-b]pyrrole-2-carboxylate
(E)-N-(3-碘-4-(3-对甲苯基丙烯酰基)苯基)乙酰胺(203mg,0.5mmol)为底物与异氰基乙酸乙酯(0.06mL),按实施例37方法,在60℃下搅拌24小时。粗产物经柱层析(10∶1石油醚∶乙酸乙酯)提纯,产率:20%。
1H NMR(CDCl3,400Hz):δ=12.93(br s,1H;NH),10.23(br s,1H;CH3CONH),8.0(d,J=1.6Hz,1H;Phenyl),7.54(d,J=8.0Hz,2H;Phenyl),7.31(d,J=8.0Hz,1H;Phenyl),7.24(dd,J=8.0Hz,1.6Hz,1H;Phenyl),7.17(d,J=8.0Hz,2H;Phenyl),4.20(q,J=7.2Hz,2H;OCH2CH3),2.34(s,3H;ArCH3),2.10(CH3CONH),1.22(t,J=7.2Hz,3H;OCH2CH3).
13CNMR(d-DMSO,100Hz):δ=185.2(-C=O),169.3(CH3CONH),160.7(COOCH2CH3),150.9,144.4,137.5,135.8,134.4,130.4,129.6,129.0,128.3,124.4,123.2,122.9,117.9,111.4,60.4(OCH2CH3),24.6(CH3CONH),21.3(ArCH3),14.6(COOCH2CH3).MS(APCI):M/Z:[M+H+]。
以下以3-(对甲苯苯基)-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯的合成为例,说明其它的例如K2CO3,K3PO4,NaOH或KOH;除DMF之外的溶剂DMSO、DMA、Dioxane、或CH3CN等;除CuI之外的铜盐例如CuBr,CuCl,CuI2,CuBr2,CuCl2,Cu(OTf)2,或Cu(OTf)2等都适合于本发明所述的合成方法,其它的含有二氢茚酮并吡咯骨架的分子的合成的数据省略,但效果等同。
实施例42
3-(对甲苯苯基)-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
氩气保护下,室温下将E-3-对甲苯苯基-1-(2-碘苯基)-2-丙烯-1-酮(MW=348,0.5mmol,175mg),异氰基乙酸乙酯(MW=113,0.55mmol,0.06mL),溴化亚铜(0.05mmol,10mg),碳酸铯(MW=325,1.0mmol,325mg)加入到密封的反应管里面,用2mLDMF溶解,室温搅拌24h后,往反应混合液加入10mL水淬灭反应,用10mL乙酸乙酯萃取3次,有机相用无水硫酸钠干燥,减压旋掉溶剂,过硅胶柱分离(淋洗液石油醚∶乙酸乙酯=8∶1),得到108mg产物,产率43%。谱图(见实施例3)。
实施例43
3-(对甲苯苯基)-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
催化剂为氯化亚铜(0.05mmol,10mg),其它和实施例42相同,得到108mg产物,产率43%,谱图(见实施例3)。
实施例44
3-(对甲苯苯基)-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
催化剂为溴化铜(0.05mmol,10mg),其它和实施例42相同,产率33%。谱图(见实施例3)。
实施例45
3-(对甲苯苯基)-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
催化剂为三氟甲磺酸亚铜(0.05mmol,10mg),其它和实施例42相同,产率43%。谱图(见实施例3)。
实施例46
3-(对甲苯苯基)-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
催化剂为三氟甲磺酸铜(0.05mmol,20mg),其它和实施例42相同,产率43%。谱图(见实施例3)。
实施例47
3-(对甲苯苯基)-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
碘亚铜(0.05mmol,10mg),其它和实施例42相同,产率61%。谱图(见实施例3)。
实施例48
3-(对甲苯苯基)-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
催化剂为醋酸亚铜(0.05mmol,5mg),其它和实施例42相同,产率36%。谱图(见实施例3)。
实施例49
3-(对甲苯苯基)-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
氩气保护下,室温下将E-3-(对甲苯苯基)-1-(2-碘苯基)-2-丙烯-1-酮(MW=348,0.5mmol,175mg),异氰基乙酸乙酯(MW=113,0.55mmol,0.06mL),碘化亚铜(0.05mmol,10mg),碳酸钾(1.0mmol,138mg)加入到密封的反应管里面,用2mLDMF溶解,室温搅拌24h后,往反应混合液加入10mL水淬灭反应,用10mL乙酸乙酯萃取3次,有机相用无水硫酸钠干燥,减压旋掉溶剂,过硅胶柱分离(淋洗液石油醚∶乙酸乙酯=8∶1),产率39%。谱图(见实施例3)。
实施例50
3-(对甲苯苯基)-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
氩气保护下,室温下将E-3-(对甲苯苯基)-1-(2-碘苯基)-2-丙烯-1-酮(MW=348,0.5mmol,175mg),异氰基乙酸乙酯(MW=113,0.55mmol,0.06mL),碘化亚铜(0.05mmol,10mg),碳酸铯(MW=325,1.0mmol,325mg)加入到密封的反应管里面,用2mL CH3CN溶解,室温搅拌24h后,往反应混合液加入10mL水淬灭反应,用10mL乙酸乙酯萃取3次,有机相用无水硫酸钠干燥,减压旋掉溶剂,过硅胶柱分离(淋洗液石油醚∶乙酸乙酯=8∶1),产率50%。谱图(见实施例3)。
实施例51
3-(对甲苯苯基)-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
氩气保护下,室温下将E-3-(对甲苯苯基)-1-(2-碘苯基)-2-丙烯-1-酮(MW=348,0.5mmol,175mg),异氰基乙酸乙酯(MW=113,0.55mmol,0.06mL),碘化亚铜(0.05mmol,10mg),碳酸铯(MW=325,1.0mmol,325mg)加入到密封的反应管里面,用2mL DMSO溶解,室温搅拌24h后,往反应混合液加入10mL水淬灭反应,用10mL乙酸乙酯萃取3次,有机相用无水硫酸钠干燥,减压旋掉溶剂,过硅胶柱分离(淋洗液石油醚∶乙酸乙酯=8∶1),产率60%。谱图(见实施例3)。
实施例52
3-(对甲苯苯基)-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
氩气保护下,室温下将E-3-(对甲苯苯基)-1-(2-碘苯基)-2-丙烯-1-酮(MW=348,0.5mmol,175mg),异氰基乙酸乙酯(MW=113,0.55mmol,0.06mL),碘化亚铜(0.05mmol,10mg),碳酸铯(MW=325,1.0mmol,325mg)加入到密封的反应管里面,用2mL DMF溶解,室温搅拌24h后,往反应混合液加入10mL水淬灭反应,用10mL乙酸乙酯萃取3次,有机相用无水硫酸钠干燥,减压旋掉溶剂,过硅胶柱分离(淋洗液石油醚∶乙酸乙酯=8∶1),产率20%。谱图(见实施例3)。
实施例53
3-(对甲苯苯基)-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
氩气保护下,室温下将E-3-(对甲苯苯基)-1-(2-碘苯基)-2-丙烯-1-酮(MW=348,0.5mmol,175mg),异氰基乙酸乙酯(MW=113,0.55mmol,0.06mL),碘化亚铜(0.05mmol,10mg),NaOH(1.0mmol,40mg)加入到密封的反应管里面,用2mLDMF溶解,室温搅拌24h后,往反应混合液加入10mL水淬灭反应,用10mL乙酸乙酯萃取3次,有机相用无水硫酸钠干燥,减压旋掉溶剂,过硅胶柱分离(淋洗液石油醚∶乙酸乙酯=8∶1),产率47%。谱图(见实施例3)。
实施例54
3-(对甲苯苯基)-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
氩气保护下,室温下将E-3-(对甲苯苯基)-1-(2-碘苯基)-2-丙烯-1-酮(MW=348,0.5mmol,175mg),异氰基乙酸乙酯(MW=113,0.55mmol,0.06mL),碘化亚铜(0.05mmol,10mg),NaOH(1.0mmol,56mg)加入到密封的反应管里面,用2mLDMF溶解,室温搅拌24h后,往反应混合液加入10mL水淬灭反应,用10mL乙酸乙酯萃取3次,有机相用无水硫酸钠干燥,减压旋掉溶剂,过硅胶柱分离(淋洗液石油醚∶乙酸乙酯=8∶1),产率43%。谱图(见实施例3)。
实施例55
3-(对甲苯苯基)-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
氩气保护下,室温下将E-3-(对甲苯苯基)-1-(2-碘苯基)-2-丙烯-1-酮(MW=348,0.5mmol,175mg),异氰基乙酸乙酯(MW=113,0.55mmol,0.06mL),碘化亚铜(0.05mmol,10mg),磷酸钾(1.0mmol,211mg)加入到密封的反应管里面,用2mLDMF溶解,室温搅拌24h后,往反应混合液加入10mL水淬灭反应,用10mL乙酸乙酯萃取3次,有机相用无水硫酸钠干燥,减压旋掉溶剂,过硅胶柱分离(淋洗液石油醚∶乙酸乙酯=8∶1),产率30%。谱图(见实施例3)。
实施例56
3-(对甲苯苯基)-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
氩气保护下,室温下将E-3-(对甲苯苯基)-1-(2-碘苯基)-2-丙烯-1-酮(MW=348,0.5mmol,175mg),异氰基乙酸乙酯(MW=113,0.5mmol,0.06mL),碘化亚铜(0.015mmol,3mg),磷酸钾(1.0mmol,211mg)加入到密封的反应管里面,用2mLDMF溶解,室温搅拌24h后,往反应混合液加入10mL水淬灭反应,用10mL乙酸乙酯萃取3次,有机相用无水硫酸钠干燥,减压旋掉溶剂,过硅胶柱分离(淋洗液石油醚∶乙酸乙酯=8∶1),产率30%。谱图(见实施例3)。
实施例57
3-(对甲苯苯基)-4-氧代1,4-二氢茚酮[1,2-b]吡咯-2-羧酸乙酯
氩气保护下,室温下将E-3-(对甲苯苯基)-1-(2-碘苯基)-2-丙烯-1-酮(MW=348,0.5mmol,175mg),异氰基乙酸乙酯(MW=113,0.5mmol,0.06mL),碘化亚铜(0.1mmol,20mg),磷酸钾(1.0mmol,211mg)加入到密封的反应管里面,用2mLDMF溶解,室温搅拌24h后,往反应混合液加入10mL水淬灭反应,用10mL乙酸乙酯萃取3次,有机相用无水硫酸钠干燥,减压旋掉溶剂,过硅胶柱分离(淋洗液石油醚∶乙酸乙酯=8∶1),产率30%。谱图(见实施例3)。
实施例58
3-p-tolyl-2-tosylindeno[1,2-b]pyrrol-4(1H)-one and 3-p-tolylindeno[1,2-b]pyrrol-4(1H)-one
3-对甲苯基-2对甲苯磺酰基茚酮[1,2-b]吡咯-4-酮(1H)和
氩气保护下,室温下将E-3-(对甲苯苯基)-1-(2-碘苯基)-2-丙烯-1-酮(MW=348,0.5mmol,175mg),对甲基苯磺酰基甲基异腈(0.5mmol,100mg),碘化亚铜(0.015mmol,3mg),碳酸钾(1.0mmol,325mg)加入到密封的反应管里面,用2mLDMF溶解,室温搅拌24h后,往反应混合液加入10mL水淬灭反应,用10mL乙酸乙酯萃取3次,有机相用无水硫酸钠干燥,减压旋掉溶剂,过硅胶柱分离(淋洗液石油醚∶乙酸乙酯=8∶1),得到化合物,40%。
1H NMR(d-DMSO,400Hz):δ=13.41(br s,1H;NH),7.55(d,J=8.0Hz,2H;Phenyl),7.46-7.7.48(m,2H;Phenyl),7.41-7.44(m,2H;Phenyl),7.33-7.38(m,3H;Phenyl),7.27-7.30(m,1H;Phenyl),7.19(d,J=7.6Hz,2H;Phenyl),2.35(s,3H;ArCH3),2.33(s,3H;ArCH3).
MS(APCI):M/Z:414.1[M+H+]。
实施例59
3-p-tolyl-2-tosylindeno[1,2-b]pyrrol-4(1H)-one and 3-p-tolylindeno[1,2-b]pyrrol-4(1H)-one
3-对甲苯基-2对甲苯磺酰基茚酮[1,2-b]吡咯-4-酮(1H)和
氩气保护下,室温下将E-3-(对甲苯苯基)-1-(2-碘苯基)-2-丙烯-1-酮(MW=348,0.5mmol,175mg),对甲基苯磺酰基甲基异腈(0.5mmol,100mg),碘化亚铜(0.015mmol,3mg),DBU(1,8-diazabicyclo[5.4.0]undec-7-ene,1.0mmol,0.3mL)加入到密封的反应管里面,用2mLDMF溶解,室温搅拌24h后,往反应混合液加入10mL水淬灭反应,用10mL乙酸乙酯萃取3次,有机相用无水硫酸钠干燥,减压旋掉溶剂,过硅胶柱分离(淋洗液石油醚∶乙酸乙酯=8∶1),得到化合物,50%。
1H NMR(d-DMSO,400Hz):δ=13.41(br s,1H;NH),7.55(d,J=8.0Hz,2H;Phenyl),7.46-7.7.48(m,2H;Phenyl),7.41-7.44(m,2H;Phenyl),7.33-7.38(m,3H;Phenyl),7.27-7.30(m,1H;Phenyl),7.19(d,J=7.6Hz,2H;Phenyl),2.35(s,3H;ArCH3),2.33(s,3H;ArCH3).
MS(APCI):M/Z:414.1[M+H+]。
Claims (6)
1.一种含有二氢茚酮并吡咯骨架的化合物的合成方法,其特征是,在有机溶剂和碱的环境中,具有式I结构的化合物与异氰基化合物在铜盐为催化剂的条件下进行串联反应,构建含有二氢茚酮并吡咯骨架的化合物;
式I
其中:
Y为I或Br;
R1选自:
1)C1~C3烷基;
2)NO2,CN,COOMe,COOH,F,Cl,Br;
3)OMe,Me,NH2,NHAc,N,N二烷基;
R2选自:
1)C1~C10烷基;
2)COOMe,COOEt,CO(CH2)n、n=1-10;
3)苯环或芳香性杂环;
4)被CH3、OMe、N,N二烷基、NH2,NHAc、OH、CN、NO2、CF3、Cl、F中一个以上取代基取代的苯环或芳香性杂环;R’为C1~C10烷基。
2.如权利要求1所述的合成方法,其特征是,所述催化剂的量为相对于异氰基化合物的用量的摩尔百分比为3%到20%。
3.如权利要求1所述的合成方法,其特征是,当Y为I时,串联反应的进行温度为20~25℃;当Y为Br时,串联反应的进行温度为60~90℃。
4.如权利要求1-3任一所述的合成方法,其特征是,所述的碱是以下无机碱中的一种:K2CO3,Cs2CO3,K3PO4,NaOH或KOH;或所述的碱为有机碱DBU;所述的有机溶剂是DMF、DMSO、DMA、Dioxane、或CH3CN。
5.如权利要求1-3任一所述的合成方法,其特征是,所述的铜盐是CuI,CuBr,CuCl,CuI2,CuBr2,CuCl2,Cu(OTf)2,或Cu(OTf)2。
6.如权利要求1所述的合成方法,其特征是,所述的异氰基化合物为异氰基乙酸乙酯或对甲基苯磺酰甲基异腈。
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CN104370795A (zh) * | 2014-10-15 | 2015-02-25 | 复旦大学 | 一种双靶向卵巢癌细胞微管蛋白及其周围血管的茚酮化合物及其制备方法与应用 |
JP2016529234A (ja) * | 2013-07-15 | 2016-09-23 | ビーエーエスエフ ソシエタス・ヨーロピアBasf Se | 殺有害生物化合物 |
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JP2016529234A (ja) * | 2013-07-15 | 2016-09-23 | ビーエーエスエフ ソシエタス・ヨーロピアBasf Se | 殺有害生物化合物 |
CN104370795A (zh) * | 2014-10-15 | 2015-02-25 | 复旦大学 | 一种双靶向卵巢癌细胞微管蛋白及其周围血管的茚酮化合物及其制备方法与应用 |
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